Myelin is a substance composed of a group of myelin-specific proteins which form a complex multilamellar sheath surrounding neuronal axons. Myelin plays a critical role in the normal functioning of the nervous system. Myelin forms early in development and its formation involves the activation of a group of unique genes. Some of these genes appear to also regulate the proliferation, migration and differentiation of Schwann cells in the peripheral nervous system, in addition to the formation of the myelin sheath.
Eighty to ninety percent of total myelin protein in the central nervous system corresponds to myelin basic proteins (MBPs) and proteolipid proteins (PLP and DM20).
Myelin in the peripheral nervous system (PNS) is mainly composed of protein zero (P.sub.0) and peripheral myelin protein 22 (PMP-22), as well as myelin basic proteins.
The complete function of myelin proteins is not entirely known. However, animals carrying specific gene mutations which encode for defective myelin proteins provide some information. For example, the MBP gene which normally encodes for a family of at least six closely related membrane proteins (14-21.5 KDa) generated by RNA splicing events is substantially missing in the shiverer mouse (shi). This defect results in the considerably reduced formation of myelin and abnormally compacted myelin sheaths in the central nervous system. However, the defect causes minimal changes in the peripheral nervous system of shi mice, suggesting that other proteins serve the functions of MBPs in the peripheral nervous system. By comparison, defects in the gene encoding P.sub.0 are known which cause hypomyelination and abnormal compaction in the peripheral nervous system.
Further, defects in the gene encoding PLP result in the jimpy mouse phenotype and human Pelizaeus-Merzbacher disease. Both diseases result in the death of oligodendrocytes and in the formation of abnormal membrane apposition in the central nervous system.
By comparison, alterations in the PMP-22 gene cause the trembler (tr) mouse phenotype, as well as the human disease Charcot-Marie-Tooth IA and hereditary neuropathy with liability to pressure palsy. In addition to being a structural myelin protein, PMP-22 appears to regulate Schwann cell proliferation since it is identical to the growth arrest-specific gene gas-3. Further, the over expression of PMP-22 inhibits growth rates in Schwann cells while the under expression of PMP-22 increases Schwann cell division rate. The central nervous system homologue to PMP-22 is currently unknown.
Besides the disorders of myelin described above, there exist many other disorders of myelin for which etiologies are not yet known. These disorders include leukodystrophies and multiple sclerosis (MS).
Multiple sclerosis is characterized by recurrent attacks of focal or multi-focal neurologic dysfunction. In addition, there exists a chronic progressive form. Neurologic dysfunction stems from discrete demyelinating lesions in the central nervous system. While multiple sclerosis can affect any age group, its onset is most commonly in early adult life. Attacks can occur frequently or infrequently. Further, the neurologic dysfunction associated with attacks can ameliorate completely or can leave a residual permanent neurologic deficit.
Multiple sclerosis is currently diagnosed on the basis of history, and on the demonstration of lesions in the central nervous system by a variety of laboratory tests including magnetic resonance imaging scans. However, a diagnosis of multiple sclerosis is frequently difficult to make because of its varied presentation.
Evidence has suggested that multiple sclerosis is an autoimmune disorder. That evidence includes studies which show that the immunization of animals with myelin proteins, as well as the adoptive transfer of activated CD4 cells specific for some myelin proteins, result in a demyelinating disease similar to multiple sclerosis. Further, acute lesions in multiple sclerosis demonstrate macrophages, T cells and deposits of immunoglobulin.
Besides multiple sclerosis, there are many autoimmune diseases which cause significant morbidity and mortality in human and animal populations. Among the human diseases believed to be autoimmune in origin are some forms of arthritis, diabetes, Grave's disease, Hashimoto's, myasthenia gravis, scleroderma and systemic lupus erythematous. Diagnosis of the various autoimmune diseases is made on the basis of history, physical exam and laboratory tests, but the diagnoses can also be difficult and imprecise.
Further, the use of synthetic peptides as antigens in the diagnosis and therapy of autoimmune and other diseases and conditions is currently the subject of considerable study. Progress in the use of synthetic peptides has been hampered, however, because of the difficulty in identifying regions of peptides which serve as epitopes. Commonly, epitopes are predicted on the bases of calculations of hydrophobic and hydrophilic amino acid content to determine which amino acids will be expressed on the cell surface. This approach has met with only limited success.
Therefore, it would be advantageous to know the central nervous homologue to PMP-22. Further, it would be advantageous to have an additional method for diagnosing or for confirming the diagnosis of multiple sclerosis. Still further, it would be advantageous to have a method for diagnosing or for confirming the diagnosis of various other autoimmune diseases. Also, it would be advantageous to have a device and method for identifying regions of peptides, proteins or protein homologues which serve as epitopes.